Quinazoline derivatives as kinase inhibitors

ABSTRACT

The present invention relates to nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which have inhibitory activity on the phosphorylation of kinases, which inhibits the activity of such kinases. The invention is also related to a method of inhibiting kinases and treating disease states in a mammal by inhibiting the phosphorylation of kinases. In a particular aspect the present invention provides nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which inhibit phosphorylation of a of a PDGF receptor to hinder abnormal cell growth and cell wandering, and a method for preventing or treating cell-proliferative diseases such as arteriosclerosis, vascular reobstruction, cancer and glomerulosclerosis.

This application claims the benefit of U.S. provisional application Ser.No. 60/226,122, filed Aug. 18, 2000.

TECHNICAL FIELD

The present invention relates to nitrogen-containing heterocycliccompounds and pharmaceutically acceptable salts thereof which haveinhibitory activity on the phosphorylation of kinases, which inhibitsthe activity of such kinases. The invention is also related to a methodof inhibiting kinases and treating disease states in a mammal byinhibiting the phosphorylation of kinases.

BACKGROUND ART

PDGF (platelet-derived growth factor) is known to act as an aggravatingfactor for cell-proliferative diseases such as arteriosclerosis,vascular reobstruction after percutaneous coronary angioplasty andbypass operation, cancer, glomerulonephritis, glomerulosclerosis,psoriasis and articular rheumatism [Cell, 46, 155-169 (1986); Science,253, 1129-1132 (1991); Nippon Rinsho (Japanese J. of Clinical Medicine),50, 3038-3045 (1992); Nephrol Dial Transplant, 10, 787-795 (1995);Kidney International, 43 (Suppl. 39), 86-89 (1993); Journal ofRheumatology, 21, 1507-1511 (1994); Scandinavian Journal of Inmmunology,27, 285-294 (1988), etc.].

As for quinazoline derivatives which are useful as drugs,N,N-dimethyl-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazine carboxamideis described as a bronchodilator in South African Patent No. 67 06512(1968). Dimethoxyquinazoline derivatives are described as inhibitors ofphosphorylation of epidermal growth factor (EGF) receptor in JapanesePublished Unexarnined Patent Application No. 208911/93 and WO 96/09294.Quinoline derivatives having benzodiazepin receptor agonist activity aredescribed in Pharmacology Biochemistry and Behavior, 53, 87-97 (1996)and European Journal of Medicinal Chemistry, 31, 417-425 (1996), andquinoline derivatives which are useful as anti-parasite agents aredescribed in Indian Journal of Chemistry, 26B, 550-555 (1987).

Inhibitors of phosphorylation of PDGF receptor so far known includebismono- and bicyclic aryl compounds and heteroaryl compounds (WO92/20642), quinoxaline derivatives [Cancer Research, 54, 6106 (1994)],pyrimidine derivatives (Japanese Published Unexamined Patent ApplicationNo. 87834/94) and dimethoxyquinoline derivatives [Abstracts of the 16thAnnual Meeting of the Pharmaceutical Society of Japan (Kanazawa) (1996),2, p. 275, 29(C2) 15-2].

Disclosure of the Invention

An object of the present invention is to provide nitrogen-containingheterocyclic compounds and pharmaceutically acceptable salts thereofwhich have inhibitory activity on the phosphorylation of kinases, whichinhibits the activity of the kinases. Particularly important kinaseinhibition according to the invention is of receptor tyrosine kinasesincluding platelet-derived growth factor (PDGF) receptor, Flt3, CSF-1R,epidermal growth factor receptor (EGRF), fibroblast growth factor (FGF),vascular endothelial growth factor receptor (VEGFR) and others. Anotherclass of kinase inhibition according to the invention is inhibitoryactivity nonreceptor tyrosine Iinases including src and abl, and thelike. A third class of kinase inhibition according to the invention isinhibitory activity toward serine/threonine kinases, including suchkinases as MAPK, MEK and cyclin dependent kinases (CDKs) that mediatecell prolifetation, AKT and CDK such that mediate cell survival and NIKthat regulate inflammatory responses. Tnhibition of such kinases can beused to treat diseases involving cell survival, proliferation andmigration, including cardiovascular disease, such as arteriosclerosisand vascular reobstruction, cancer, glomerulosclerosis fibrotic diseasesand inflammation, as well as the general treatment of cell-proliferativediseases.

In a preferred embodiment, the present invention provides compounds andpharmaceutically acceptable salts thereof which inhibit or preventinhibition of phosphorylation of at least one PDGF receptor by at leastone tyrosine kinase. Such PDGF receptor kinase inhibition can hinderabnormal cell growth and cell wandering, and thus such compounds areuseful for the prevention or treatment of cell-proliferative diseasessuch as arteriosclerosis, vascular reobstruction, cancer andglomerulosclerosis.

The present invention relates to nitrogen-containing heterocycliccompounds represented by formula I as follows:

wherein

-   R¹ is a member selected from the group consisting of:    -   —CN, —X, —CX₃, —R⁵, —CO₂R⁵, —C(O)R⁵, —SO₂R⁵, —O—C₁₋₈ alkyl that        is straight or branched chained, —O-phenyl, —O-naphthyl,        —O-indolyl and —O-isoquinolinyl;-   X is a halogen;-   R⁵ is hydrogen or a Cl₁₋₈, alkyl that is straight or branched    chained;-   R² and R⁴ are each independently a member selected from the group    consisting of:    -   —O—CH₃, —O—CH₂—CH₃, —O—CH₂—CH═CH₂, —O—CH₂—C≡CH,        —O(CH₂)_(n)—SO₂—R⁵, —O—CH₂—CH(R₆)CH₂—R³ and —O(—CH₂)_(n)—R³;-   R⁶ is —OH, —X, or a C₁₋₈ alkyl that is straight or branched chained;-   n is 2 or 3;-   R³ is a member selected from the group consisting of:-   —OH, —O—CH₃, —O—CH₂—CH₃, —NH₂, —N(—CH₃)₂, —NH(—CH₂-phenyl),    —NH(-Phenyl), —CN

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Particularly preferred compounds according to formula above are suchcompounds wherein R¹ is a member selected from the group consisting ofCN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy, and position isomers and homologs thereof, and allpharmaceutically acceptable isomers, salts, hydrates, solvates andprodrug derivatives of such compounds.

Also, particularly preferred are such compounds wherein R² and R⁴ aredifferent and one of R² and R⁴ is —O—CH₃, and all pharmaceuticallyacceptable isomers salts, hydrates, solvates and prodrug derivatives ofsuch compounds.

The pharmaceutically acceptable salts of the compounds according toformula (I) include pharmaceutically acceptable acid addition salts,metal salts, animonium salts, organic amine addition salts, amino acidaddition salts, etc.

Examples of the pharmaceutically acceptable acid addition salts of thecompounds of formula (I) are inorganic acid addition salts such ashydrochloride, sulfate and phosphate, and organic acid addition saltssuch as acetate, maleate, fumarate, tartrate, citrate andmethanesulfonate.

Examples of the pharmaceutically acceptable metal salts are alkali metalsalts such as sodium salt and potassium salt, alkaline earth metal saltssuch as magnesium salt and calcium salt, aluminum salt and zinc salt.Examples of the pharmaceutically acceptable ammonium salts are ammoniumsalt and tetramethyl ammonium salt. Examples of the pharmaceuticallyacceptable organic amine addition salts include heterocyclic amine saltssuch as morpholine and piperidine salts. Examples of thepharmaceutically acceptable amino acid addition salts are salts withlysine, glycine and phenylalanine.

In a preferred embodiment the invention provides compounds according toformula I(a) and formula I(b) as follows:

wherein

-   R¹ is a member selected from the group consisting of:-   —CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl,    —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy,    5-indolyloxy, 5-isoquinolyloxy; and all pharmaceutically acceptable    isomers, salts, hydrates, solvates and prodrug derivatives thereof.

In another preferred embodiment the invention provides compoundsaccording to formula (Ic) and formula (Id) as follows:

wherein

-   R¹ is a member selected from the group consisting of:-   —CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl,    —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy,    5-indolyloxy, 5-isoquinolyloxy; and all pharmaceutically acceptable    isomers, salts, hydrates, solvates and prodrug derivatives thereof.

In still another preferred embodiment the invention provides compoundsaccording to formula I(e) and formula I(f) as follows:

wherein

-   R¹ is a member selected from the group consisting of:-   —CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl,    —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy,    5-indolyloxy, 5-isoquinolyloxy; and all pharmaceutically acceptable    isomers, salts, hydrates, solvates and prodrug derivatives thereof.

In yet another preferred embodiment the invention provides compoundsaccording to formula I(g) and formula I(h) as follows:

wherein

-   n is 2 or 3; and-   R¹ is a member selected from the group consisting of:-   —CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl,    —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy,    5-indolyloxy, 5-isoquinolyloxy;-   R₃ is a member selected from the group consisting of:-   —OH, —O—CH₃, —O—CH₂—CH₃, —NH₂, —N(—CH₃)₂, —NH(—CH₂-phenyl),    —NH(-Phenyl), —CN    and all pharmaceutically acceptable isomers, salts, hydrates,    solvates and prodrug derivatives thereof.

The pharmaceutically acceptable salts of the compounds according toformula (I) include pharmaceutically acceptable acid addition salts,metal salts, ammonium salts, organic amine addition salts, amino acidaddition salts, etc.

The present invention is not limited by the above listed compounds.Analogs of the bicyclic compounds are contemplated.

Further, an especially preferred embodiment of the present invention isa compound selected from the group consisting of:N-(4-indol-5-yloxyphenyl){4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}carboxamide

N-(4-indol-4-yloxyphenyl){4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}carboxamide

{4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-(4-naphthyloxyphenyl)carboxamide

{4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-(4-(2-naphthyloxy)phenyl)carboxamide

N-(4-(5-isoquinolyloxy)phenyl){4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}carboxamide

{4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-(4-phenoxyphenyl)carboxamide

{4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl)(4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl)carboxamide

{4-[6-methoxy-7-(2-piperidylethoxy)quinazolin-4-yl]piperazinyl}-N-[4-methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[6-methoxy-7-(2-piperidylethoxy)quinazolin-4-yl]piperazinyl}carboxamide

{4-[6-methoxy-7-(3-piperidylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]piperazinyl}carboxamide

{4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[6-methoxy-7-(2-(1,2,3,4-tetraazol-2-yl)ethoxy)quinazolin-4-yl]piperazinyl}carboxamide

N-(4-cyanophenyl){4-[6-methoxy-7-(2-(1,2,3,4-tetraazolyl)ethoxy)quinazolinyl]piperazinyl}carboxamide

{4-[6-methoxy-7-(2-(1,2,3,4-tetraazolyl)ethoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[6-methoxy-7-(2-(1,2,3,4-tetraazol-2-yl)ethoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

(4-{7-[3-(4,4-difluoropiperidyl)propoxy}-6-methoxyquinazolin-4-yl]piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide

{4-[6-methoxy-7-(3-piperazinylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl)(4-{6-methoxy-7-[3-(4-methylpiperazinyl)propoxy]quinazolin-yl}piperazinyl)carboxamide

N-(4-cyanophenyl){4-[6-methoxy-7-(3-(1,4-thiazaperhydroin-4-yl)propoxy)quinazolin-4-yl]piperazinyl}corboxamide

(4-{7-[3-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))propoxy]-6-methoxyquinazolin-4-yl}piperazinyl)-N-(4-cyanophenyl)carboxamide

N-(4-cyanophenyl)[4-(7-ethoxy-6-methoxyquinazolin-4-yl)piperazinyl]carboxamide

[4-(7-ethoxy-6-methoxyquinazolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide

[4-(7-ethoxy-6-methoxyquinazolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide

[4-(7-ethoxy-6-methoxyquinazolin-4-yl)piperazinyl]-N-(4-indol-4-yloxyphenyl)carboxamide

[4-(7-ethoxy-6-methoxyquinazolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide

N-(4-cyanophenyl)[4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl)piperazinyl]carboxamide

[4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide

[4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide

N-(4-indol-4-yloxyphenyl)[4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl)piperazinyl]carboxamide

[4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide

N-(4-cyanophenyl)[4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl)piperazinyl]carboxamide

[4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl)piperazinyl]-N-[4-(methylethoxy))phenyl]carboxamide

[4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide

N-(4-indol-4-yloxyphenyl)[4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl)piperazinyl]carboxamide

[4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide

(4-{6-methoxy-7-[3-(2-methylpiperidyl)propoxy]quinazolin-4-yl}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide

(4-{6-methoxy-7-[3-(4-methylpiperidyl)propoxy]quinazolin-4-yl}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl)(4-{6-methoxy-7-[3-(2-methylpiperidyl)propoxy]quinazolin-4-yl}piperazinyl)carboxamide

N-(4-cyanophenyl)(4-{6-methoxy-7-[3-(4-methylpiperidyl)propoxy]quinazolin-4-yl}piperazinyl)carboxamide

{4-[7-(2-hydroxy-3-piperidylpropoxy-6-methoxyquinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[7(2-fluoro-3-piperidylpropoxy)-6-methoxyquinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

[4-(6-methoxy-7-{3-[(2-methylpropyl)sulfonyl]propoxy}quinazolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide

(4-{6-methoxy-7-[3-(propylsulfonyl)propoxy]quinazolin-4-yl)piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide

methyl4-({4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}carbonylamino)benzoate

N-(4-acetylphenyl){4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}carboxamide

N-(4-bromophenyl){4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}carboxamide

{4-[6-methoxy-7-(3-pyrrolidinylpropoxy)qunazolin-4-yl]piperazinyl}-N-[4-(trifluoromethyl)phenyl]carboxamide

{4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}-N-(4-methylphenyl)carboxamide

{4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylsulfonyl)phenyl]carboxamide

N-(4-fluorophenyl){4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}carboxamide

4-({4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}carbonylamino)benzoicacid

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Preparation of Compounds

The compounds may be prepared using methods and procedures as generallydescribed in WO 98/14431 published Sep. 12, 1998, which is incorporatedherein by reference. Starting materials may be made or obtained asdescribed therein as well. Leaving groups such as halogen, lower alkoxy,lower alkylthio, lower alkylsulfonyloxy, arylsulfonyloxy, etc, may beutilized when necessary except for the reaction point, followed bydeprotection. Suitable amino protective groups are, for example, thosedescribed in T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons Inc. (1981), etc., such as ethoxycarbonyl,t-butoxycarbonyl, acetyl and benzyl. The protective groups can beintroduced and eliminated according to conventional methods used inorganic synthetic chemistry [e.g., T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons Inc. (1981)].

In such processes, if the defined groups change under the conditions ofthe working method or are not appropriate for carrying out the method,the desired compound can be obtained by using the methods forintroducing and eliminating protective groups which are conventionallyused in organic synthetic chemistry [e.g., T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons Inc. (1981)], etc.Conversion of functional groups contained in the substituents can becarried out by known methods [e.g., R. C. Larock, Comprehensive OrganicTransformations (1989)] in addition to the above-described processes,and some of the active compounds of formula I may be utilized asintermediates for further synthesizing novel derivatives according toformula I.

The intermediates and the desired compounds in the processes describedabove can be isolated and purified by purification methodsconventionally used in organic synthetic chemistry, for example,neutralization, filtration, extraction, washing, drying, concentration,recrystallization, and various kinds of chromatography. Theintermediates may be subjected to the subsequent reaction withoutpurification.

There may be tautomers for some formula I, and the present inventioncovers all possible isomers including tautomers and mixtures thereof.Where chiral carbons lend themselves to two different enantiomers, bothenantiomers are contemplated as well as procedures for separating thetwo enantiomers.

In the case where a salt of a compound of formula I is desired and thecompound is produced in the form of the desired salt, it can besubjected to purification as such. In the case where a compound offormula I is produced in the free state and its salt is desired, thecompound of formula I is dissolved or suspended in a suitable organicsolvent, followed by addition of an acid or a base to form a salt.

The following non-limiting reaction Schemes I and II illustratepreferred embodiments of the invention with respect to making compoundsaccording to the invention.

This synthesis of atert-butyl-4-[6-methoxy-7-(phenyhnethoxy)quinazolin-4-yl]-piperazinecarboxylate compound, provides an intermediate that can be utilized inthe synthesis of various compounds (the scheme can be adapted to producebicyclic position isomers) as described above for formula I. Thevanillic acid is benzylated, followed by nitration with fuming nitricacid at about 100° C. The nitro functionality is reduced with a reducingagent such as tin chloride, and the like, followed by cyclization with abase such as formamide at elevated temperature, preferably in the range100 to 200° C. to afford quinazolinone. The synthesis of4-Cl-quinazoline is effected by treating quinazolinone with halogenatingreagents such as thionyl chloride, oxalyl chloride and phosphorousoxychloride in presence of solvent such as toluene, or carbontetrachloride. This intermediate is obtained by treating4-Cl-quinazoline with Boc-piperazine in an appropriate solvent, such asisopropanol, acetonitrile, or THF at room or reflux temperature for 1-6h in presence of base triethylamine or pyridine.

This illustrated Scheme III provides the synthesis of varioussubstituted urea intermediates from the intermediate obtained in SchemeI, or by other procedures. The intermediate form Scheme I (or itsbicyclic position isomer) is debenzylated under hydrogenation conditionsfollowed by alkylation with various substituted allyl halides.Deprotection of Boc group is effected by trifluoroacetic acid followedby treatment with various isocyanates to afford the final ureacompounds. In cases where the isocyanates are not commerciallyavailable, the piperazine intermediate may be treated with phosgene togive a carbamoyl chloride intermediate followed by reaction with varioussubstituted anilines. The piperazine intermediate can also be treatedwith p-nitrophenyl chloroformate to afford a nitrophenyl carbamateintermediate that can be treated with various anilines to afford thedesired ureas. If the urea compound has a terminal NH₂ group (or one ormore of the hydrogen atoms on this amino group is replaced by adisplaceable substituent), then this compound may be utilized anintermediate compound with which to produce a urea compound terminatedwith a —NH-phenyl-R¹ groups. Alternatively, if a different R¹ group isdesired on the phenyl group, a replaceable para position leaving groupphenyl substituent may be displaced after coupling to provide theparticular R¹ substituent as described for formula I, above.

Such procedures for producing the claimed compounds are merely anillustration of a preferred aspect of the invention. Other proceduresand adaptations will be apparent to one of ordinary skill in the artupon views these reaction schemes and the structures of the compoundsaccording to the invention. Such procedures are deemed to be within thescope of the present invention.

Also, the compounds of formula I and phannaceutically acceptable saltsthereof may exist in the form of adducts with water (hydrates) orvarious solvents, which are also within the scope of the presentinvention.

The following non-limiting examples are provided to better illustratethe present invention.

EXAMPLE 1

The intermediatetert-butyl-4-[6-methoxy-7-(2-piperidylethoxy)quinazolin-4-yl]-piperazinecarboxylate:

was prepared using the procedures as generally described in reactionSchemes I and II as follows:

Step A: To the DMF (300 mL) solution of the vanillic acid (25 g, 149mmol), was added K₂CO₃ (102.7 g, 744 mmol, BnBr (44.2 g, 372 mmol), andthe resulting suspension was stirred at room temperature overnight. Thereaction mixture was filtered, EtOAc was added and the solution waswashed with brine, dried, and concentrated. Purification on silica gelchromatography gave 55 g(96%) of the intermediate product. MS(ES) 349(M+H)⁺

Step B: To the CH₂Cl₂ solution (100 mL) of benzyl protected materialfrom Step A (20 g, 57.4 mmol) at −10° C. was slowly added acetic acid(100 mL). To this cold solution slowly added conc. HNO₃ (25.8 mL, 574.4mmol) and the reaction was warmed to room temperature, followed byreflux overnight at 100° C. After overnight poured the reaction intoice, extracted the product with EtOAc and washed with brine and driedwith MgSO4. The solvent was removed in vacuo to afford the desiredintermediate product as a yellow solid (21.8 g, 96.5%). MS(ES) 416(M+Na).

Step C: To the EtOAc solution (100 mL) of nitro material from Step B(10.9 g, 27.7 mmol) added SnCl₂.H₂O (18.7 g, 83.1 mmol) and the reactionmixture was heated at 50° C. overnight. After cooling the reactionmixture was filtered through celite, and the filtrate was washed with10% NaHCO₃, extracted with EtOAc. The organic layers dried, evaporatedto afford the intermediate amino product as a brown solid (9.5 g, 95%).MS(ES) 364 (M+H).

Step D: The amino product (3 g, 8.3 mmol) from Step C was dissolved informamide (20 mL) to this was added ammonium formate (781 mg, 12.4 mmol)and the reaction mixture was heated at 150° C. for 4h. During thisperiod entire starting material was consumed by HPLC (high performanceliquid chromatography), after cooling poured the reaction into water toafford creamy precipitate. The precipitate was collected by filtration,which is the desired intermediate, cyclized7-benzyloxy-6-methoxy-4-quinazolinone (1.9 g, 81%). MS(ES) 283(M+H).

Step E: A mixture of 7-benzyloxy-6-methoxy-4-quinazolinone (1 g, 3.5mmol, from Step D), thionyl chloride (5 mL) and DMF (5drops) was heatedat reflux for 4 h. After cooling excess thionyl chloride was removed byevaporation and the residue azeotroped with toluene to afford theintermediate, 4-chloro-6-methoxy-7-benzyloxyquinazoline, as a yellowsolid (652 mg, 62%). MS(ES) 301 (M+H).

Step F: To the THF solution (20 mL) of4-chloro-6-methoxy-7-benzyloxyquinazoline (1.8 g, 6 mmol) addedBoc-piperazine (2.2 g, 12 mmol) followed by DIEA (4.2 mL, 24 mmol) andheated the reaction overnight at 50° C. The solvent was evaporated, theresidue dissolved in water and extracted the product with EtOAc. TheEtOAc layer was dried, filtered and evaporated to give the intermediatetert-butyl4-[6-methoxy-7-phenylmethoxy)quinazolin-4-yl]piperazinecarboxylate as awhite solid (2.2 g, 81%). MS(ES) 451 (M+H).

Step G: The benzyloxy compound from Step F (500 mg, 1.1 mmol) wasdissolved in EtOH (5 mL), to this added Pd(OH)₂/C (50 mg) and themixture was placed on the Parr hydrogenator at 50 psi H₂ pressure forovernight. The reaction mixture was filtered through celite and washedwith EtOH, then evaporated the solvent to afford the intermediatedebenzylated material (400 mg, 98%). MS(ES) 361 (M+H)

Step H: To the DMF solution (10 mL) of tert-butyl4-(7-hydroxy-6-methoxyquinazolin-4-yl)piperazinecarboxylate (1.8 g, 5mmol), Cs₂CO₃ (3.3 g, 10 mmol) added 1-chloroethyl-tosylate (1.8 mL, 10mmol). The mixture was stirred overnight at room temperature. Thesolvent was evaporated and the crude residue was purified by RP-HPLC(reverse-phase high performance liquid chromatography) to afford theintermediatetert-butyl-4-[6-methoxy-7-(2-chloroethoxy)quinazolin-4-yl]piperazinecarboxylateas the desired product (850 mg, 40%). MS(ES) 423 (M+H)

Step I: To the DMF solution (10 mL) of the starting material (450 mg,1.2 mmol) from Step H added piperidine (1.2 mL, 12 mmol) and thereaction was heated at 80° C. overnight. The solvent was evaporated andthe crude residue was purified by RP-HPLC to affordtert-butyl-4-[6-methoxy-7-(2-piperidylethoxy)quinazolin-4-yl]piperazinecarboxylateas the desired product (310 mg, 55%). MS(ES) 472 (M+H).

EXAMPLE 2

N-(4-cyanophenyl){4-[6-methoxy-7-(2-piperidylethoxy)quinazolin-4-yl]piperazinyl}carboxanide:

was prepared using the intermediate obtained in Example 1 and theprocedures as generally described in reaction Schemes II as follows:

Totert-butyl-4-[6-methoxy-7-(2-piperidylethoxy)quinazolin-4-yl]piperazine-carboxylate(from Example 1 (Step I), 111 mg, 0.3 mmol) added 4N HCl/dioxane (1 ml)and the reaction was stirred at room temperature for 1 h. The solventwas evaporated and azetroped with pentane several times to afford debocmaterial, i.e. material with the Boc protecting group removed. To thisresidue was added DMF (2 ml), followed by 4-cyanophenylisocyanate (75mg, 0.45 mmol) and the reaction was stirred at rt. overnight. Thesolvent was evaporated and residue purified by RP-HPLC to afford desiredproduct N-(4-cyanophenyl){4-[6-methoxy-7-(2-piperidylethoxy)quinazolin-4-yl]piperazinyl}carboxamideas a white solid (89 mg, 59%). MS (ES) 516(M+H).

EXAMPLES 3-4

N-(4-cyanophenyl){4-[6-methoxy-7-(2-(methoxy)ethoxy)quinazolin-4-yl]piperazinyl}carboxamide:

was prepared using the procedures as described above in Examples 1 and 2except that 1-bromoethylmethyl ether was used instead of1-chloroethyltosylate as an alkylating reagent, to provide the titlecompound, in a comparable yield to that described in Examples 1 and 2.

The pharmacological activities of the compounds of the present inventionare obtained by following the test example procedures as follows, forexample.

Biological Test Assay Type 1

Inhibitory effect on compounds on Autophosphorylation of PlateletDerived Growth Factor β-PDGF receptor

(1) HR5 Phosphorylation Assay

The HR5 cell line is a cell line of CHO cells engineered to overexpresshurnan β-PDGFR, which cell line is available from the ATCC. Theexpression level of β-PDGFR in HR5 cells is around 5×10⁴ receptor percell. For the phosphorylation assay according to the invention, HR5cells were grown to confluency in 96-well microtiter plates understandard tissue culture conditions, followed by serum-starvation for 16hours. Quiescent cells were incubated at 37° C. without or withincreasing concentrations of the test compound (0.01-30 uM) for 30minutes followed by the addition of 8 nM PDGF BB for 10 minutes. Cellswere lysed in 100 mM Tris, pH7.5, 750 mM NaCl, 0.5% Triton X-100, 10 mMsodium pyrophosphate, 50 mM NaF, 10 ug/ml aprotinin, 10 ug/ml leupeptin,1 mM phenylmethylsulfonyl fluoride, 1 mM sodium vanadate, and the lysatewas cleared by centrifuigation at 15,000×g for 5 minutes. Clarifiedlysates were transferred into a second microtiter plate in which thewells were previously coated with 500 ng/well of 1B5B11 anti-β-PDGFRmAb, and then incubated for two hours at room temperature. After washingthree times with binding buffer (0.3% gelatin, 25 mM Hepes pH 7.5, 100mM NaCl, 0.01% Tween-20), 250 ng/ml of rabbit polyclonalanti-phosphotyrosine antibody (Transduction Laboratory) was added andplates were incubated at 37° C. for 60 minutes. Subsequently, each wellwas washed three times with binding buffer and incubated with 1 ug/ml ofhorse radish peroxidase-conjugated anti-rabbit antibody (BoehringerMannheim) at 37° C. for 60 minutes. Wells were washed prior to addingABTS (Sigma), and the rate of substrate formation was monitored at 650nm. The assay results are reported as IC₅₀ (expressed as theconcentration of a compound according to the invention that inhibits thePDGF receptor phosphorylation by 50%) as compared to control cells thatare not exposed to a compound according to the invention.

Examples of such IC₅₀ test results in the HR5 assay for compoundsaccording to the invention are set forth below in Table 1.

(2) MG63 Phosphorylation Assay

The MG63 cell line is a human osteosarcoma tumor cell line availablefrom the ATCC. This assay is for measuring endogenous β-PDGFRphosphorylation in MG63 cells. The assay conditions are the same asthose described at for HR5 cell, except that PDGF-BB stimulation isprovided in the presence or absence of 45% human plasma. The HR5 assayresults are reported as an IC₅₀ (expressed as the concentration of acompound according to the invention that inhibits the PDGF receptorphosphorylation by 50%) as compared to control cells that are notexposed to a compound according to the invention.

Examples of such IC₅₀ test results in the MG63 assay for compoundsaccording to the invention are set forth below in Table 1.

The assay results for Compound Examples 2 and 4 are set forth in Table 1below.

TABLE 1 MG63 w/human plasma HR5 Example Compound IC₅₀ (μM) IC₅₀ (μM)Example 2 0.080 0.360 Example 4 0.700 1.5Biological Test Assay Type 2Growth Inhibition Against Smooth Muscle Cells

Vascular smooth muscle cells are isolated from a pig aorta byexplanation and used for the test. The cells are put into wells of a96-well plate (8000 cells/well) and cultured in Dulbeccois modifiedEagle's medium (DMEM; Nissui Pharmaceutical Co., Ltd.) containing 10%fetal bovine serum (FBS; Hyclone) for 4 days. Then, the cells arefuirther cultured in DMEM containing 0.1% FBS for 3 days, and aresynchronized at the cell growth stationary phase.

To each well is added DMEM containing 0.1% FBS and a test sample at avaried concentration, and the cell growth is brought about by PDGF-BB(SIGMA, final concentration: 20 ng/ml). After culturing for 3 days, thecell growth is measured using a cell growth assay kit (BoehringerMannheim) according to the XTT method [J. Immunol. Methods, 142, 257-265(1991)], and the cell growth score is calculated by the followingequation.

Cell growth score=100×{1−(M−PO)/(P100−PO)} wherein P100=absorbance byXTT reagent when stimulated by PDGF-BB; PO=absorbance by XTT reagentwhen not stimulated by PDGF-BB, and M=absorbance by XTT reagent afteraddition of a sample when stimulated by PDGF-BB.

The test result is expressed as the concentration of a test compoundwhich inhibits the cell growth by 50% (IC₅₀).

Biological Test Assay Type 3

Inhibitory Effect on Lypertrophy of Vascular Intimia

Male SD rats (weight: 375-445 g, Charles River, golden standard) areanesthetized with sodium pentobarbital (50 mg/kg, i.p.), and then theneck of each animal is incised by the median incision, followed byretrograde insertion of a balloon catheter (2F, Edwards Laboratories)into the left external carotid. After the above treatment is repeatedseven times, the catheter is pulled out, the left external carotid isligated, and the wound is sutured. A test compound is suspended in a0.5% solution of Tween 80 in an aqueous solution of sodium chloride to aconcentration of 20 mg/ml in the case of intraperitoneal administrationand in a 0.5% solution of methyl cellulose 400 to a concentration of 6mg/ml in the case of oral administration. The suspension is administeredonce a day in the case of intraperitoneal administration and once ortwice a day in the case of oral administration for a period of 15 daysstarting on the day before the balloon injury. On the 14th day after theballoon injury, the animal is killed and its left carotid is extirpated.The tissues are fixed with formalin, wrapped in paraffin and sliced,followed by Elastica Wangeeson staining. The area of the cross sectionof the vascular tissues (intima and media) is measured with an imageanalyzer (Luzex F, NIRECO) and the intima/media area ratio (I/M) isregarded as the degree of hypertrophy of the vascular intima.

From the results obtained, it is apparent when the hypertrophy ofvascular intima is significantly inhibited by administration of thecompounds of the present invention.

Biological Test Assay Type 4

Evaluation by the Use of a Rat Adjuvant Arthritis Model

Dead cells of Mycobacteriuni bacterium (Difco Laboratories Inc.) aredisrupted in agate mortar and suspended in liquid paraffin to the finalconcentration of 6.6 mg/ml, followed by sterilization with high pressuresteam. Then, 100 ml of the suspension is subcutaneously injected intothe right hind foot pad of each animal of groups of female 8-weeks-oldLewis rats (Charles River Japan) (6 animals/group) to induce adjuvantarthritis. A test compound is suspended in a 0.5% solution of methylcellulose to the final concentration of 3 mg/ml, and from just beforethe induction of arthritis, the suspension is orally administered in anamount of 100 ml/100 g of the body weight once a day, 5 days a week. Toa control group is administered a 0.5% solution of methyl cellulose. Anormal group is given no adjuvaut treatment or test compoundadministration. The administration of the test compound is continuedtill the 18th day after the adjuvant treatment. On the 17th day, thenumber of leukocytes in peripheral blood are counted, and on the 18thday, all the blood is collected, followed by dissection.

The change in body weight with the passage of time, the change of edemain hind foot with the passage of time, the weight of spleen and thymus,the number of leukocytes in peripheral blood, the hydroxyproline contentof urine, the glucosaminoglycan content of urine, the SH concentrationin serum, the concentration of nitrogen monoxide in serum and theconcentration of mucoprotein in serum are measured and evaluated. Thevolume of each of both hind feet are measured using a rat's hind footedema measurement device (TK-101, Unicom). The number of leukocytes inperipheral blood are counted using an automatic multichannel blood cellcounter (Sysmex K-2000, Toa Iyo Denshi Co., Ltd.). The hydroxyprolinecontent of urine is measured according to the method described in Ikeda,et al., Annual Report of Tokyo Metropolitan Research Laboratories P. H.,36, 277 (1985), and the glucosaminoglycan content is measured accordingto the method described in Moriyama, et al., Hinyo Kiyo, 40, 565 (1994)and Klompmakers, et al., Analytical Biochemistry, 153, 80 (1986). The SHconcentration in serum is measured according to the method described inMiesel, et al., Inflanunation, 17, 595 (1993), and the concentration ofnitrogen monoxide is measured according to the method of Tracey, et al.,Journal of Pharmacology & Experimental Therapeutics, 272, 1011 (1995).The concentration of mucoprotein is measured using Aspro GP Kit (OtsukaPharmaceutical Co., Ltd.). The percentage inhibition for each indicationis calculated according to the following equation.% Inhibition={(Control group−Compound-administered group)/(Controlgroup−Normal group)}×100.

From the results obtain from such assays, it is apparent when thecompound according to the invention inhibits the occurrence of adjuvantarthritis.

Biological Test Assay Type 5

Activity On a Mesangial Proliferative Gloimierulonephritis Model

Anti-rat Thy-1.1 monoclonal antibody OX-7 (Sedaren) is administered tomale Wister-Kyoto rats (Charles River Japan, 160 g, 6 animals/group) inan amount of 1.0 mg/kg by intravenous administration through the tailvein. A test compound is suspended in a 0.5% solution of methylcelluloseand the resulting suspension is administered to each of the rats twice aday for a period of 7 days starting on the day before the administrationof OX-7. On the 7th day after the OX-7 administration, when mesangialcell growth and extracellular matrix hypertrophy become prominent, theleft kidney of each rat is extirpated, fixed with 20% buffered formalinfor 6 hours and wrapped in paraffin, followed by slicing. The obtainedpieces are subjected to immune tissue staining using antibody PC10(DAKO) against an intranuclear antigen of proliferative cells. Aftercomparative staining with Methyl Green staining solution usingdiaminobenzidine as a color developer, the paraffin pieces are enclosed.Half of the glomeruli in a kidney piece are observed and the number ofthe cells in one glomerulus which are positive to the intranuclearantigen of proliferative cells are calculated. The test for thesignificance of difference is carried out by the Wilcoxon test.

From such results, it is apparent when the compounds according to thepresent invention show alleviating activity on mesangial proliferativeglomerulonephritis.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof can be administered as such, but it is usually preferred toadminister them in the form of pharmaceutical compositions, which areused for animals and human beings.

It is preferred to employ the administration route which is the mosteffective for the treatment. For example, administration is made orallyor non-orally by intrarectal, intraoral, subcutaneous, intramuscular orintravenous administration.

Examples of the forms for administration are capsules, tablets,granules, powders, syrups, emulsions, suppositories and injections.

Liquid compositions such as emulsions and syrups which are appropriatefor oral administration can be prepared using water, sugars such assucrose, sorbitol and fructose, glycols such as polyethylene glycol andpropylene glycol, oils such as sesame oil, olive oil and soybean oil,preservatives such as benzoates, flavors such as strawberry flavor andpeppermint, etc.

Capsules, tablets, powders and granules can be prepared using excipientssuch as lactose, glucose, sucrose and mannitol, disintegrating agentssuch as starch and sodium alginate, lubricants such as magnesiumstearate and talc, binders such as polyvinyl alcohol, hydroxypropylcellulose and gelatin, surfactants such as fatty acid esters,plasticizers such as glycerin, etc.

Compositions suitable for non-oral administration preferably comprise asterilized aqueous preparation containing an active compound which isisotonic to the recipient's blood. For example, injections are preparedusing a carrier which comprises a salt solution, a glucose solution, ora mixture of a salt solution and a glucose solution.

Compositions for topical application are prepared by dissolving orsuspending an active compound in one or more kinds of solvents such asmineral oil, petroleum and polyhydric alcohol, or other bases used fortopical drugs.

Compositions for intestinal administration are prepared using ordinarycarriers such as cacao fat, hydrogenated fat and hydrogenated fatcarboxylic acid, and are provided as suppositories.

The compositions for non-oral administration may additionally beformulated to contain one or more kinds of additives selected fromglycols, oils, flavors, preservatives (including antioxidants),excipients, disintegrating agents, lubricants, binders, surfactants andplasticizers which are used for the preparation of compositions for oraladministration.

The effective dose and the administration schedule for each of thecompounds of formula (I) or a pharmaceutically acceptable salt thereofwill vary depending on the administration route, the patient's age andbody weight, and the type or degree of the diseases to be treated.However, it is generally appropriate to administer a compound of formula(I) or a pharmnaceutically acceptable salt thereof in a dose of0.01-1000 mg/adult/day, preferably 5-500 mg/adult/day, in one to severalparts.

All the compounds of the present invention can be immediately applied tothe treatment of kinase-dependent diseases of mammals as kinaseinhibitors, specifically, those relating to tyrosine kinase.Specifically preferred are the compounds which have IC₅₀ within therange of 10 nM-10 μM. Even more preferred are compounds which have IC₅₀within the range of 10 nM to −1 μM. Most preferred are compounds whichhave an IC₅₀ value which is less than 1 μM.

Specific compounds of the present invention which have an activity tospecifically inhibit one of the three types of protein kinase (forexample, kinase which phosphorylates tyrosine, kinase whichphosphorylates tyrosine and threonine, and kinase which phosphorylatesthreonine) can be selected. Tyrosine kinase-dependent diseases includehyperproliferative malfunction which is caused or maintained by abnormaltyrosine kinase activity. Examples thereof include psoriasis, pulmonaryfibrosis, glomerulonephritis, cancer, atherosclerosis andanti-angiopoiesis (for example, tumor growth and diabetic retinopathy).Current knowledge of the relationship between other classes of kinaseand specific diseases is insufficient. However, compounds havingspecific PTK-inhibiting activity have a useful treatment effect. Otherclasses of kinase have also been recognized in the same manner.Quercetin, genistein and staurosporin, which are all PTK-inhibitors,inhibit many kinds of protein kinase in addition to tyrosine kinase.However, as a result of their lack of the specificity, theircytotoxicity is high. Therefore, a PTK-inhibitor (or an inhibitor ofother classes of Icinase) which is apt to bring about undesirable sideeffects because of the lack of selectivity can be identified by the useof an ordinary test to measure cytotoxicity.

In view of the above description it is believed that one of ordinaryskill can practice the invention. The examples given above arenon-limiting in that one of ordinary skill in view of the above willreadily envision other permutations and variations on the inventionwithout departing from the principal concepts. Such permutations andvariations are also within the scope of the present invention.

Although the present invention has been described in some detail by wayof illustration for purposes of clarity of understanding, it will beapparent to those of ordinary skill in the art that variousmodifications and equivalents can be made without departing from thespirit and scope of the invention. It should be understood that theforegoing discussion and examples merely present a detailed descriptionof certain preferred embodiments. All the patents, journal articles andother documents discussed or cited above are herein incorporated byreference in their entirety.

1. A compound selected from the group consisting of:

wherein R¹ is a member selected from the group consisting of: CN,O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy, and position isomers thereof; n is 2 or 3; R₃ is amember selected from the group consisting of: —OH, —O—CH₃, —O—CH₂—CH₃,—NH₂, —N(—CH₃)₂, —NH(—CH₂-phenyl), —NH(-Phenyl), —CN

and all pharmaceutically acceptable isomers, salts, hydrates, andsolvates thereof.
 2. The compound of claim 1, having formula I(a) orformula I(b):

wherein R¹ is a member selected from the group consisting of CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolytoxy, and position isomers thereof, and all pharmaceuticallyacceptable isomers, salts, hydrates, and solvates and thereof.
 3. Thecompound of claim 1 having formula I(c) or formula I(d):

wherein R¹ is a member selected from the group consisting of CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy, and position isomers and homologs thereof, and allpharmaceutically acceptable isomers, salts, hydrates, and solvates. 4.The compound of claim 1, having formula I(e) or formula I(f):

wherein R¹ is a member selected from the group consisting of CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy, and position isomers thereof, and all pharmaceuticallyacceptable isomers, salts, hydrates, and solvates thereof.
 5. Thecompound of claim 1, having formula I(g) or formula I(h):

wherein n is 2 or 3; R¹ is a member selected from the group consistingof CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl,—O-butyl,—O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy,5-indolyloxy, 5-isoquinolyloxy, and position isomers thereof, R₃ is amember selected from the group consisting of: —OH, —O—CH₃, —O—CH₂—CH₃,—NH₂, —N(—CH₃)₂, —NH(—CH₂-phenyl), —NH(-Phenyl), —CN

and all pharmaceutically acceptable isomers, salts, hydrates andsolvates thereof.
 6. A compound according to claim 1, selected from thegroup consisting of:N-(4-indol-5-yloxyphenyl)4[6-methoxy7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl)carboxamide

N-(4-indol-4-yloxyphenyl)(4-[6-methoxy-7-(2methoxyethoxy)quinazolin-4-yl]piperazinylcarboxamide

{4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-(4-(2-naphthyloxy)phenyl)carboxamide

N-(4-(5-isoquinolyloxy)phenyl){4-[6-methoxy-7-(2-methoxyethoxy-4-yl]piperazinyl}carboxamide

{4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N(4-cyanophenyl){4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}carboxamide

{4-[6-methoxy-7-(2-piperidylethoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[6-methoxy-7-(2-piperidylethoxy)quinazolin-4-yl]piperazinyl)carboxamide

{4-[6-methoxy-7-(3-piperidylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]piperazinyl)carboxamide

{4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl)}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[6-methoxy-7-(2-(1,2,3,4-tetraazol-2-yl)ethoxy)quinazolin-4-yl]piperazinyl}carboxamide

N-(4-cyanophenyl){4-[6-methoxy-7-(2-(1,2,3,4-tetraazolyl)ethoxy)quinazolin-4-yl]piperazinyl}carboxamide

{4-[6-methoxy-7-(2-(1,2,3,4-tetraazolyl)ethoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[6-methoxy-7-(2-(1,2,3,4-tetraazol-2-yl)ethoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

(4-{7-[3-(4,4-difluoropiperidyl)propoxy]-6-methoxyquinazolin-4-yl}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxanide

{4-[6-methoxy-7-(3-piperazinylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl)(4-{6-methoxy-7-[3-(4-methylpiperazinyl)propoxy]quinazolin-4-yl)piperazinyl)carboxamide

N-(4-cyanophenyl){4-[6-methoxy-7-(3-(1,4-thiazaperhydroin-4-yl)propoxy)quinazolin-4-yl]piperazinyl)carboxamide

(4-{7-[3-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))propoxy]-6-methoxyquinazolin-4-yl}piperazinyl)-N-(4-cyanopheny)carboxamide

N-(4-cyanophenyl)[4-(7-ethoxy-6-methoxyqumazolin-4-yl)piperazinyl]carboxamide

[4-(7-ethoxy-6-methoxyquinazolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide

[4-(7-ethoxy-6-methoxyquinazolin-4-yl)piperazinyl]-N-(4-indol-4-yloxyphenyl)carboxamide

(4-{6-methoxy-7-[3-(2-methylpiperidyl)propoxy]quinazolin-4-yl}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide

(4-{6-methoxy-7-[3-(4-methylpiperidyl)propoxy]quinazolin-4-yl}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl)(4-{6-methoxy-7-[3-(2-methylpiperidyl)propoxy]quinazolin-4-yl}piperazinyl)carboxaxmide

N-(4-cyanophenyl)(4-{6-methoxy-7-[3-(4-methylpiperidyl)propoxy]quinazolin-4-yl}piperazinyl)carboxamide

and all pharmaceutically acceptable isomers, salts, hydrates, solvates.7. A pharmaceutical composition comprising an effective amount of acompound according to claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable diluent or carrier.
 8. Acompound according to claim 1, having the following formula:


9. A compound according to claim 1, having the following formula:


10. A compound according to claim 1, having the following formula:


11. A compound according to claim 1, having the following formula: